Pub Date : 2024-11-01DOI: 10.1016/S0968-0004(24)00238-X
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(24)00238-X","DOIUrl":"10.1016/S0968-0004(24)00238-X","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages i-ii"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.08.005
Seyun Kim , Rashna Bhandari , Charles A. Brearley , Adolfo Saiardi
Combinatorial substitution of phosphate groups on the inositol ring gives rise to a plethora of inositol phosphates (InsPs) and inositol pyrophosphates (PP-InsPs). These small molecules constitute an elaborate metabolic and signalling network that influences nearly every cellular function. This review delves into the knowledge accumulated over the past decades regarding the biochemical principles and significance of InsP metabolism. We focus on the biological actions of InsPs in mammals, with an emphasis on recent findings regarding specific target proteins. We further discuss the roles of InsP metabolism in contributing to physiological homeostasis and pathological conditions. A deeper understanding of InsPs and their metabolic pathways holds the potential to address unresolved questions and propel advances towards therapeutic applications.
{"title":"The inositol phosphate signalling network in physiology and disease","authors":"Seyun Kim , Rashna Bhandari , Charles A. Brearley , Adolfo Saiardi","doi":"10.1016/j.tibs.2024.08.005","DOIUrl":"10.1016/j.tibs.2024.08.005","url":null,"abstract":"<div><div>Combinatorial substitution of phosphate groups on the inositol ring gives rise to a plethora of inositol phosphates (InsPs) and inositol pyrophosphates (PP-InsPs). These small molecules constitute an elaborate metabolic and signalling network that influences nearly every cellular function. This review delves into the knowledge accumulated over the past decades regarding the biochemical principles and significance of InsP metabolism. We focus on the biological actions of InsPs in mammals, with an emphasis on recent findings regarding specific target proteins. We further discuss the roles of InsP metabolism in contributing to physiological homeostasis and pathological conditions. A deeper understanding of InsPs and their metabolic pathways holds the potential to address unresolved questions and propel advances towards therapeutic applications.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 969-985"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.08.002
Bocheng Wu , Angela N. Koehler , Peter M.K. Westcott
Immune checkpoint blockade (ICB) therapies, which block inhibitory receptors on T cells, can be efficacious in reinvigorating dysfunctional T cell responses. However, most cancers do not respond to these therapies and even in those that respond, tumors can acquire resistance. New strategies are needed to rescue and recruit T cell responses across patient populations and disease states. In this review, we define mechanisms of T cell dysfunction, focusing on key transcription factor (TF) networks. We discuss the complex and sometimes contradictory roles of core TFs in both T cell function and dysfunction. Finally, we review strategies to target TFs using small molecule modulators, which represent a challenging but highly promising opportunity to tune the T cell response toward sustained immunity.
免疫检查点阻断(ICB)疗法可阻断T细胞上的抑制性受体,从而有效重振功能失调的T细胞反应。然而,大多数癌症对这些疗法没有反应,即使有反应的肿瘤也会产生抗药性。我们需要新的策略来挽救和招募不同患者群体和疾病状态下的 T 细胞应答。在这篇综述中,我们定义了 T 细胞功能障碍的机制,重点关注关键转录因子 (TF) 网络。我们讨论了核心 TF 在 T 细胞功能和功能障碍中复杂且有时相互矛盾的作用。最后,我们回顾了使用小分子调节剂靶向 TFs 的策略,这是调整 T 细胞反应以实现持续免疫的一个极具挑战性但又大有希望的机会。
{"title":"New opportunities to overcome T cell dysfunction: the role of transcription factors and how to target them","authors":"Bocheng Wu , Angela N. Koehler , Peter M.K. Westcott","doi":"10.1016/j.tibs.2024.08.002","DOIUrl":"10.1016/j.tibs.2024.08.002","url":null,"abstract":"<div><div>Immune checkpoint blockade (ICB) therapies, which block inhibitory receptors on T cells, can be efficacious in reinvigorating dysfunctional T cell responses. However, most cancers do not respond to these therapies and even in those that respond, tumors can acquire resistance. New strategies are needed to rescue and recruit T cell responses across patient populations and disease states. In this review, we define mechanisms of T cell dysfunction, focusing on key transcription factor (TF) networks. We discuss the complex and sometimes contradictory roles of core TFs in both T cell function and dysfunction. Finally, we review strategies to target TFs using small molecule modulators, which represent a challenging but highly promising opportunity to tune the T cell response toward sustained immunity.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 1014-1029"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.09.004
Wenqiang Chen , Valdemar Brimnes Ingemann Johansen , Cristina Legido-Quigley
Emerging evidence links type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD), with brain insulin resistance (BIR) as a key factor. In a recent study, Lanzillotta et al. reveal that reduced biliverdin reductase-A (BVR-A) impairs glycogen synthase kinase 3β (GSK3β) phosphorylation, causing mitochondrial dysfunction and exacerbating brain insulin resistance in the progression of both T2DM and AD.
越来越多的证据表明,2 型糖尿病(T2DM)和阿尔茨海默病(AD)之间存在联系,而脑胰岛素抵抗(BIR)是其中的一个关键因素。在最近的一项研究中,Lanzillotta 等人发现,胆绿素还原酶-A(BVR-A)的减少会损害糖原合成酶激酶 3β (GSK3β)的磷酸化,导致线粒体功能障碍,并在 T2DM 和 AD 的进展过程中加剧脑胰岛素抵抗。
{"title":"Bridging brain insulin resistance to Alzheimer’s pathogenesis","authors":"Wenqiang Chen , Valdemar Brimnes Ingemann Johansen , Cristina Legido-Quigley","doi":"10.1016/j.tibs.2024.09.004","DOIUrl":"10.1016/j.tibs.2024.09.004","url":null,"abstract":"<div><div>Emerging evidence links type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD), with brain insulin resistance (BIR) as a key factor. In a recent study, <span><span>Lanzillotta <em>et al.</em></span><svg><path></path></svg></span> reveal that reduced biliverdin reductase-A (BVR-A) impairs glycogen synthase kinase 3β (GSK3β) phosphorylation, causing mitochondrial dysfunction and exacerbating brain insulin resistance in the progression of both T2DM and AD.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 939-941"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.08.006
Suzanne A. Weijers , Michiel Vermeulen , Katarzyna W. Kliza
ADP-ribosylation regulates numerous fundamental cellular processes in health and disease. However, the limited availability of suitable tools and methods prevents the identification and characterization of certain components of the ADP-ribosylation signaling network and, consequently, efficient utilization of their biomedical potential. Identification of ADP-ribose (ADPr) readers has been particularly impeded by challenges associated with the development of ADPr-based enrichment probes. These difficulties were finally overcome in several recent studies describing various approaches to identifying ADPr readers in an unbiased, proteome-wide manner. In this review we discuss these different strategies and their limitations, benefits and drawbacks, and summarize how these technologies contribute to a dissection of ADP-ribosylation signaling networks. We also address unmet technological needs and future directions to investigate interactions with ADPr linkages.
{"title":"The quest to identify ADP-ribosylation readers: methodological advances","authors":"Suzanne A. Weijers , Michiel Vermeulen , Katarzyna W. Kliza","doi":"10.1016/j.tibs.2024.08.006","DOIUrl":"10.1016/j.tibs.2024.08.006","url":null,"abstract":"<div><div>ADP-ribosylation regulates numerous fundamental cellular processes in health and disease. However, the limited availability of suitable tools and methods prevents the identification and characterization of certain components of the ADP-ribosylation signaling network and, consequently, efficient utilization of their biomedical potential. Identification of ADP-ribose (ADPr) readers has been particularly impeded by challenges associated with the development of ADPr-based enrichment probes. These difficulties were finally overcome in several recent studies describing various approaches to identifying ADPr readers in an unbiased, proteome-wide manner. In this review we discuss these different strategies and their limitations, benefits and drawbacks, and summarize how these technologies contribute to a dissection of ADP-ribosylation signaling networks. We also address unmet technological needs and future directions to investigate interactions with ADPr linkages.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 1000-1013"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.08.004
Thibault Houles , Sang-Oh Yoon , Philippe P. Roux
Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation.
{"title":"The expanding landscape of canonical and non-canonical protein phosphorylation","authors":"Thibault Houles , Sang-Oh Yoon , Philippe P. Roux","doi":"10.1016/j.tibs.2024.08.004","DOIUrl":"10.1016/j.tibs.2024.08.004","url":null,"abstract":"<div><div>Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 986-999"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.07.007
Germán Rivas , Allen P. Minton
A large fraction of soluble protein within the interior of living cells may reversibly associate with structural elements, including proteinaceous fibers and phospholipid membranes. In this opinion, we present theoretical and experimental evidence that many of these associations are due to nonspecific attraction between the protein and the surface of the fiber or membrane, and that such associations may lead to substantial changes in the association state of the adsorbed proteins, the biological function of the adsorbed proteins, and the distribution of these proteins between the many microenvironments existing within the cell.
{"title":"Surfaces as frameworks for intracellular organization","authors":"Germán Rivas , Allen P. Minton","doi":"10.1016/j.tibs.2024.07.007","DOIUrl":"10.1016/j.tibs.2024.07.007","url":null,"abstract":"<div><div>A large fraction of soluble protein within the interior of living cells may reversibly associate with structural elements, including proteinaceous fibers and phospholipid membranes. In this opinion, we present theoretical and experimental evidence that many of these associations are due to nonspecific attraction between the protein and the surface of the fiber or membrane, and that such associations may lead to substantial changes in the association state of the adsorbed proteins, the biological function of the adsorbed proteins, and the distribution of these proteins between the many microenvironments existing within the cell.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 942-954"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tibs.2024.09.002
Yuri Shibata
Targeted protein degradation is an innovative therapeutic modality for the degradation of disease-causing proteins. In a recent report combining high-throughput screening of small-molecule compounds and biochemical analyses, Mori et al. identified certain inhibitors of cellular pathways, such as PARylation and proteostatic pathways, which enhance proteolysis-targeting chimera (PROTAC)-induced protein degradation.
{"title":"Efficient PROTAC-ing: combinational use of PROTACs with signaling pathway inhibitors","authors":"Yuri Shibata","doi":"10.1016/j.tibs.2024.09.002","DOIUrl":"10.1016/j.tibs.2024.09.002","url":null,"abstract":"<div><div>Targeted protein degradation is an innovative therapeutic modality for the degradation of disease-causing proteins. In a recent report combining high-throughput screening of small-molecule compounds and biochemical analyses, <span><span>Mori <em>et al.</em></span><svg><path></path></svg></span> identified certain inhibitors of cellular pathways, such as PARylation and proteostatic pathways, which enhance proteolysis-targeting chimera (PROTAC)-induced protein degradation.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 11","pages":"Pages 936-938"},"PeriodicalIF":11.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.tibs.2024.06.012
Sally M. Kephart , Nancy Hom , Kelly K. Lee
Protein-mediated membrane fusion is the dynamic process where specialized protein machinery undergoes dramatic conformational changes that drive two membrane bilayers together, leading to lipid mixing and opening of a fusion pore between previously separate membrane-bound compartments. Membrane fusion is an essential stage of enveloped virus entry that results in viral genome delivery into host cells. Recent studies applying cryo-electron microscopy techniques in a time-resolved fashion provide unprecedented glimpses into the interaction of viral fusion proteins and membranes, revealing fusion intermediate states from the initiation of fusion to release of the viral genome. In combination with complementary structural, biophysical, and computation modeling approaches, these advances are shedding new light on the mechanics and dynamics of protein-mediated membrane fusion.
{"title":"Visualizing intermediate stages of viral membrane fusion by cryo-electron tomography","authors":"Sally M. Kephart , Nancy Hom , Kelly K. Lee","doi":"10.1016/j.tibs.2024.06.012","DOIUrl":"10.1016/j.tibs.2024.06.012","url":null,"abstract":"<div><div>Protein-mediated membrane fusion is the dynamic process where specialized protein machinery undergoes dramatic conformational changes that drive two membrane bilayers together, leading to lipid mixing and opening of a fusion pore between previously separate membrane-bound compartments. Membrane fusion is an essential stage of enveloped virus entry that results in viral genome delivery into host cells. Recent studies applying cryo-electron microscopy techniques in a time-resolved fashion provide unprecedented glimpses into the interaction of viral fusion proteins and membranes, revealing fusion intermediate states from the initiation of fusion to release of the viral genome. In combination with complementary structural, biophysical, and computation modeling approaches, these advances are shedding new light on the mechanics and dynamics of protein-mediated membrane fusion.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"49 10","pages":"Pages 916-931"},"PeriodicalIF":11.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}